It has been confirmed that a KCNQ channel has five subtypes including KCNQ1, KCNQ2, KCNQ3, KCNQ4, and KCNQ5. Among them, KCNQ2-5 other than KCNQ1 are expressed in the nociceptive sensory system such as spinal dorsal root ganglion and spinal cord. The activation of the KCNQ2-5 channels causes hyperpolarization of nerve cells in a nociceptive signal pathway.
It has been reported that a KCNQ2-5 channel activator is useful for treating many disorders characterized by abnormal neuronal excitability including epilepsy, pain, migraine, and anxiety disorder (see Non-Patent Document 1). In fact, retigabine which is a KCNQ2-5 channel activator has already been marketed as an antiepileptic drug.
Further, it has also been recently reported that retigabine is useful for treating bladder disorder (overactive bladder or the like) (see Non-Patent Documents 2 and 3).
Overactive bladder is considered to be caused by a state of potential overactivity of the detrusor muscle, and therefore, a muscarinic receptor antagonist mainly having a suppressive action on bladder contraction has been widely used for its treatment. However, the muscarinic receptor is present not only in the bladder but also in the salivary gland, the intestinal tract, the ciliary muscle, and the like, and the muscarinic receptor has also a functional role. Therefore, adverse effects such as dry mouth, constipation, and blurred vision sometimes occur, and also there is a concern that the suppressive action on bladder contraction of the muscarinic receptor antagonist may cause adverse effects such as difficulty in urination, an increase in the amount of residual urine, and urinary retention, and it cannot be said that a satisfactory therapeutic effect is always achieved. Further, as a drug to overcome the problems of the muscarinic receptor antagonist, a selective β3 adrenergic receptor agonist was put on the market in 2011 in Japan. It is suggested that the selective β3 adrenergic receptor agonist hardly affects the urination function while enhancing the urine collection function by a bladder relaxing action, and it exhibits the bladder relaxing action independent of contraction stimulation, and therefore is expected to work in a wide range of patients. On the other hand, the risk of QT extension increases with an increase in the dose and it shows a heart rate increasing action by acting on the cardiac β receptor, and therefore, these are limiting factors for the dose.
From the above, in this field, a drug which has a bladder relaxing action independent of contraction stimulation and is free from fear of adverse effects has been demanded, and a KCNQ2-5 channel activator is expected as a drug which responds to these unmet medical needs.
Until now, as a KCNQ activator having an indane skeleton, for example, a compound represented by the general formula (a) is known (see Patent Document 1).
(wherein Ga is —O—, —S—, or the like; na is 1, 2, or 3; Ara1 is independently a 5- to 10-membered monocyclic or bicyclic aromatic group optionally containing one to four heteroatoms independently selected from N, O, and S; Ra1 and Ra2 are independently selected from H, CN, a halogen, CH2CN, OH, NO2, and the like; Ua is N or CRa′; Ra′, Ra3, and Ra4 are independently H, a halogen, trifluoromethyl, or the like; Xa is O or S; Ya is O or S; Za is H, a halogen, OH, C1-6 alkyl, or the like; qa is 1 or 0; Ra5 is C1-6 alkyl, Ara2, (CHR6a)waAra2, or the like, wherein wa is 0 to 3, and each Ara2 is independently a 5- to 10-membered monocyclic or bicyclic aromatic group optionally containing one to four cyclic heteroatoms independently selected from N, O, and S; and R6a is H or C1-3 alkyl (the definitions of the groups are partially extracted).
However, the compound of the present invention is not included in the general formula (a) of Patent Document 1. Further, Patent Document 1 does not describe or suggest a technique for converting the compound described in Patent Document 1 into the compound of the present invention.